Targeting Replication Stress in Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancers (TNBCs) are highly aggressive, characterized by lack of expression of progesterone, human epidermal growth factor 2, and estrogen receptors. Although they comprise only 15% of all invasive breast cancers, they often strike younger women and offer the worst prognosis of any breast cancer subtypes. These cancers also have the highest risk of metastasizing to the bone or to the lung. The current treatment for TNBCs are platinum-based therapies and currently no targeted therapy is available. It is thus imperative to identify new drugs to treat this deadly disease. A characteristic feature of TNBCS is an unstable genome, resulting in many DNA breaks and chromosomes linking together. One important structure in our DNA that protects our genome is telomeres. Telomeres are DNA repeats that cap the ends of all chromosomes and are essential to maintain genome stability. Normal cells without functional telomeres become sick and die. Cancer cells on the other hand evolved new pathways to maintain their telomeres in a healthy state, which is the main reason cancer cells are immortal. Because of their repetitive nature, telomeres are difficult regions of DNA to copy when a cell divides. We discovered that all TNBCs examined have problems replicating their telomeres and experience increased telomere replication stress. Since these cells divide very rapidly, we reasoned that TNBCs must generate protein(s) to help them replicate their telomeres. We discovered that the protein Claspin helps TNBCs replicate their telomeres. We made the exciting discovery that removing Claspin from TNBC leads to loss of cell growth and induces cell death. Importantly, normal cells and non-triple-negative breast cancer cells are not affected by Claspin loss, suggesting that Claspin is specifically required by TNBCs to replicate telomeres. Based on these preliminary results, we hypothesize that Claspin endows TNBCs with unique survival advantages by helping them replicate telomeres. We reasoned that disruption of Claspin s interaction with telomeres might be one way to induce TNBC cell death. To test this hypothesis, we propose two specific aims. In Aim 1, we will examine whether removing Claspin from telomeres reduces the rate of telomere replication. We will measure the speed of replication on individual telomeres in the presence or absence of Claspin. Completion of this aim will provide detailed information on how Claspin help resolve telomere replication stress in TNBCs. We want to develop drugs that disrupt Claspin s ability to replicate telomeres in TNBCs. We discovered that Claspin binds to a protein called TRF2 that resides on telomeres, and that this interaction is essential for Claspin s telomere replication function. We discovered a molecule called compound 33 that inhibits Claspin s binding to TRF2. We are very excited that compound 33 potently kills TNBCs in vitro but spares normal cells. In Aim 2 we will test compound 33 s tumor-inhibiting effects on two mouse models that we generated: a TNBC xenograft SCID mouse model and our MMTV-Cre^ER; Pot1a^delta/-; p53^delta/delta breast cancer model that faithfully recapitulates salient features of human TNBCs. In addition to compound 33, we will also test two existing drugs, VX970 and AZD7762, individually or in combination with compound 33. These drugs inhibit the ATR/CHK1 pathway, which is potently activated when cells cannot replicate their DNA. We believe that our proposal is very exciting and highly significant because it exploits a specific weakness of TNBCs: telomere replication stress. Using compound 33 and ATR/CHK1 inhibitors to enhance telomere replication stress to induce TNBC death is a highly novel concept. Our studies highlight therapeutic advances that are potentially paradigm changing for the treatment of patients with TNBC in the clinic. Compound 33 might prove to be the first targeted therapy against TNBCs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210099
Entities
People
- Sandy Chang
Organizations
- United States Army
- Yale University